RESUMO
Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
Assuntos
Antineoplásicos , Neoplasias , Adulto , Humanos , Animais , Camundongos , Quinases Ciclina-Dependentes , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Apoptose , Pontos de Checagem do Ciclo Celular , Modelos Animais de Doenças , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Quinase 9 Dependente de Ciclina , Neoplasias/tratamento farmacológicoRESUMO
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Clostridioides difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Quinolinas/farmacologia , Isomerases de Aminoácido/genética , Isomerases de Aminoácido/metabolismo , Animais , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clostridioides difficile/enzimologia , Clostridioides difficile/genética , Clostridioides difficile/crescimento & desenvolvimento , Desenho de Fármacos , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/patologia , Feminino , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Compostos Heterocíclicos com 2 Anéis/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Compostos de Fenilureia/síntese química , Pirróis/síntese química , Quinolinas/síntese química , Especificidade da Espécie , Relação Estrutura-Atividade , Análise de SobrevidaRESUMO
A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.
Assuntos
Antitrombinas/síntese química , Benzeno/síntese química , Desenho de Fármacos , Trombina/antagonistas & inibidores , Antitrombinas/química , Antitrombinas/farmacologia , Benzeno/química , Benzeno/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Assuntos
Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Antitrombinas/síntese química , Antitrombinas/química , Antitrombinas/farmacocinética , Disponibilidade Biológica , Cloretos , Cristalografia por Raios X , Cães , Compostos Férricos/farmacologia , Imidazóis/química , Imidazóis/farmacocinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Tempo de Tromboplastina Parcial , Ratos , Relação Estrutura-Atividade , Trombina/química , Trombina/metabolismo , Tripsina/metabolismoRESUMO
Despite their relatively weak basicity, simple azoles, specifically imidazoles and aminothiazoles, can function as potent surrogates for the more basic amines (e.g., alkyl amines, amidines, guanidines, etc.) which are most often employed as the P1 ligand in the design of noncovalent small molecule inhibitors of thrombin.
Assuntos
Azóis/farmacologia , Inibidores Enzimáticos/farmacologia , Trombina/antagonistas & inibidores , Azóis/química , Desenho de Fármacos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Tripsina/efeitos dos fármacosRESUMO
Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Pirazinas/química , Piridonas/química , Alanina/química , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Mimetismo Molecular , Oligopeptídeos , Ligação Proteica , Pirazinas/farmacocinética , Piridonas/farmacocinética , Radioimunoensaio , Relação Estrutura-AtividadeRESUMO
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Piridonas/química , Piridonas/farmacologia , Tiadiazinas/química , Tiadiazinas/farmacologia , Trombina/antagonistas & inibidores , Acetamidas/farmacocinética , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Compostos Férricos/toxicidade , Humanos , Modelos Moleculares , Piridonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacologia , Tiadiazinas/farmacocinética , Trombose/induzido quimicamente , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacocinética , Inibidores da Tripsina/farmacologiaRESUMO
Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.
Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indóis/química , Indóis/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Compostos Aza/farmacocinética , Cães , Inibidores Enzimáticos/farmacocinética , Humanos , Indóis/farmacocinética , Modelos Moleculares , Tempo de Tromboplastina Parcial , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/metabolismo , Tripsina/metabolismoRESUMO
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.